Spinal Muscular Atrophy: Why Do Low Levels of Survival Motor Neuron Protein Make Motor Neurons Sick?

Overview

Journal Nat Rev Neurosci

Specialty Neurology

Date 2009 Jul 9

PMID 19584893

Citations 384

Authors

Arthur H M Burghes

Christine E Beattie

Affiliations

Soon will be listed here.

Abstract

Many neurogenetic disorders are caused by the mutation of ubiquitously expressed genes. One such disorder, spinal muscular atrophy, is caused by loss or mutation of the survival motor neuron1 gene (SMN1), leading to reduced SMN protein levels and a selective dysfunction of motor neurons. SMN, together with partner proteins, functions in the assembly of small nuclear ribonucleoproteins (snRNPs), which are important for pre-mRNA splicing. It has also been suggested that SMN might function in the assembly of other ribonucleoprotein complexes. Two hypotheses have been proposed to explain the molecular dysfunction that gives rise to spinal muscular atrophy (SMA) and its specificity to a particular group of neurons. The first hypothesis states that the loss of SMN's well-known function in snRNP assembly causes an alteration in the splicing of a specific gene (or genes). The second hypothesis proposes that SMN is crucial for the transport of mRNA in neurons and that disruption of this function results in SMA.

Citing Articles

Clinical and Genetic Profiles of 5q- and Non-5q-Spinal Muscular Atrophy Diseases in Pediatric Patients.

Nishio H, Niba E, Saito T, Okamoto K, Lee T, Takeshima Y Genes (Basel). 2024; 15(10).

PMID: 39457418 PMC: 11506990. DOI: 10.3390/genes15101294.

Outcomes of early-treated infants with spinal muscular atrophy: A multicenter, retrospective cohort study.

Goedeker N, Rogers A, Fisher M, Arya K, Brandsema J, Farah H Muscle Nerve. 2024; 70(6):1247-1256.

PMID: 39370660 PMC: 11560615. DOI: 10.1002/mus.28267.

Glucose and Lipid Metabolism Disorders in Adults with Spinal Muscular Atrophy Type 3.

Miletic M, Stevic Z, Vujovic S, Rakocevic J, Tomic A, Tancic Gajic M Diagnostics (Basel). 2024; 14(18).

PMID: 39335757 PMC: 11431033. DOI: 10.3390/diagnostics14182078.

Recent Progress in Gene-Targeting Therapies for Spinal Muscular Atrophy: Promises and Challenges.

Haque U, Yokota T Genes (Basel). 2024; 15(8).

PMID: 39202360 PMC: 11353366. DOI: 10.3390/genes15080999.

Current developments of gene therapy in human diseases.

Liu F, Li R, Zhu Z, Yang Y, Lu F MedComm (2020). 2024; 5(9):e645.

PMID: 39156766 PMC: 11329757. DOI: 10.1002/mco2.645.

References

Cobben J, van der Steege G, Grootscholten P, de Visser M, Scheffer H, Buys C . Deletions of the survival motor neuron gene in unaffected siblings of patients with spinal muscular atrophy. Am J Hum Genet. 1995; 57(4):805-8. PMC: 1801497. View

Tritschler F, Eulalio A, Helms S, Schmidt S, Coles M, Weichenrieder O . Similar modes of interaction enable Trailer Hitch and EDC3 to associate with DCP1 and Me31B in distinct protein complexes. Mol Cell Biol. 2008; 28(21):6695-708. PMC: 2573232. DOI: 10.1128/MCB.00759-08. View

Jedrzejowska M, Borkowska J, Zimowski J, Kostera-Pruszczyk A, Milewski M, Jurek M . Unaffected patients with a homozygous absence of the SMN1 gene. Eur J Hum Genet. 2008; 16(8):930-4. DOI: 10.1038/ejhg.2008.41. View

Man N, Humphrey E, Lam L, Fuller H, Lynch T, Sewry C . A two-site ELISA can quantify upregulation of SMN protein by drugs for spinal muscular atrophy. Neurology. 2008; 71(22):1757-63. DOI: 10.1212/01.wnl.0000313038.34337.b1. View

Lefebvre S, Burlet P, Liu Q, Bertrandy S, Clermont O, Munnich A . Correlation between severity and SMN protein level in spinal muscular atrophy. Nat Genet. 1997; 16(3):265-9. DOI: 10.1038/ng0797-265. View

Pellizzoni L . Chaperoning ribonucleoprotein biogenesis in health and disease. EMBO Rep. 2007; 8(4):340-5. PMC: 1852756. DOI: 10.1038/sj.embor.7400941. View

Rossoll W, Jablonka S, Andreassi C, Kroning A, Karle K, Monani U . Smn, the spinal muscular atrophy-determining gene product, modulates axon growth and localization of beta-actin mRNA in growth cones of motoneurons. J Cell Biol. 2003; 163(4):801-12. PMC: 2173668. DOI: 10.1083/jcb.200304128. View

Grimmler M, Bauer L, Nousiainen M, Korner R, Meister G, Fischer U . Phosphorylation regulates the activity of the SMN complex during assembly of spliceosomal U snRNPs. EMBO Rep. 2004; 6(1):70-6. PMC: 1299218. DOI: 10.1038/sj.embor.7400301. View

Zapletalova E, Hedvicakova P, Kozak L, Vondracek P, Gaillyova R, Marikova T . Analysis of point mutations in the SMN1 gene in SMA patients bearing a single SMN1 copy. Neuromuscul Disord. 2007; 17(6):476-81. DOI: 10.1016/j.nmd.2007.03.003. View

10.

Matera A, Terns R, Terns M . Non-coding RNAs: lessons from the small nuclear and small nucleolar RNAs. Nat Rev Mol Cell Biol. 2007; 8(3):209-20. DOI: 10.1038/nrm2124. View

11.

Kotani T, Sutomo R, Sasongko T, Sadewa A, Gunadi , Minato T . A novel mutation at the N-terminal of SMN Tudor domain inhibits its interaction with target proteins. J Neurol. 2007; 254(5):624-30. DOI: 10.1007/s00415-006-0410-x. View

12.

Murray L, Comley L, Thomson D, Parkinson N, Talbot K, Gillingwater T . Selective vulnerability of motor neurons and dissociation of pre- and post-synaptic pathology at the neuromuscular junction in mouse models of spinal muscular atrophy. Hum Mol Genet. 2007; 17(7):949-62. DOI: 10.1093/hmg/ddm367. View

13.

Di Penta A, Mercaldo V, Florenzano F, Munck S, Ciotti M, Zalfa F . Dendritic LSm1/CBP80-mRNPs mark the early steps of transport commitment and translational control. J Cell Biol. 2009; 184(3):423-35. PMC: 2646547. DOI: 10.1083/jcb.200807033. View

14.

Kashima T, Manley J . A negative element in SMN2 exon 7 inhibits splicing in spinal muscular atrophy. Nat Genet. 2003; 34(4):460-3. DOI: 10.1038/ng1207. View

15.

Pu W, Krapivinsky G, Krapivinsky L, Clapham D . pICln inhibits snRNP biogenesis by binding core spliceosomal proteins. Mol Cell Biol. 1999; 19(6):4113-20. PMC: 104370. DOI: 10.1128/MCB.19.6.4113. View

16.

Terns M, Terns R . Macromolecular complexes: SMN--the master assembler. Curr Biol. 2001; 11(21):R862-4. DOI: 10.1016/s0960-9822(01)00517-6. View

17.

Burghes H . Other forms of survival motor neuron protein and spinal muscular atrophy: an opinion. Neuromuscul Disord. 2008; 18(1):82-3. DOI: 10.1016/j.nmd.2007.09.001. View

18.

Meister G, Fischer U . Assisted RNP assembly: SMN and PRMT5 complexes cooperate in the formation of spliceosomal UsnRNPs. EMBO J. 2002; 21(21):5853-63. PMC: 131082. DOI: 10.1093/emboj/cdf585. View

19.

DiDonato C, Lorson C, De Repentigny Y, Simard L, Chartrand C, Androphy E . Regulation of murine survival motor neuron (Smn) protein levels by modifying Smn exon 7 splicing. Hum Mol Genet. 2001; 10(23):2727-36. DOI: 10.1093/hmg/10.23.2727. View

20.

Gabanella F, Butchbach M, Saieva L, Carissimi C, Burghes A, Pellizzoni L . Ribonucleoprotein assembly defects correlate with spinal muscular atrophy severity and preferentially affect a subset of spliceosomal snRNPs. PLoS One. 2007; 2(9):e921. PMC: 1976558. DOI: 10.1371/journal.pone.0000921. View